N, n&#39;-substituted diamine compounds and method of making the same



p nd nd to t United States Patent 9 T DMMHQEC M oUNDs Anset P; Swain, Springfield: Township, Mon gomery Gounty, Pa, assignor to. -McNeil hahoratolzies lncon porated; Bhiladelphizglw, a corporation ft Bennsylvania. 10

N Drawing: APBlimfiQm-Deceluh 1.951952 Seuansot atam- The. p esent. inv n ion elates to: navel... chemi d et r p, ag

m r par icul r y methyl). ethylenediami ymp hc y ic. pron here. ar mntr in, thefli e a llli an ailable on he m ket certainv chemical hich'n saess sympatholytic properties, that. S, t 1* to p e nt he. ac i nssqf, p uep .1: hormones in, the. unmarr ed a or. prevent the actiyity of tern. These agentsposs' wh h verely t risit het 1 m hyl piperi na, eii ny u at d, ylav an benziodiexany methvl pip l ner or exampl ly b minis ered by injec ion. 5 have Qn n ransien eitec s gainst. t ul tinsg p nepht ne Suc wmpquads are ot e f cti e int -bl ck a; he. sy aa het erner ous ys em udare en; oxic h efiectivegtheyalie; not usefu 've do O e ompounds, while p sses... ympa e y icptopettiest r i y injec i since they hat a t no fle n he tom ch 2 19; nte ina wa k orally.

An important advantage of the novel compounds-of he pr sen nvention: s: that then-do noe'at d ce toxic effects that have been observedfol-lowin t-either parenteral or oral administration; of other sympatholytic agents; that is, they do not produce nausea, vomiting, tissue irritation coronary constriction, and; the; liketefiects on theheart, blood vessels-,- and; viscera.

The principal objectof present 'inuention, toeprovide new chemicabcompolmds; possessing advantageous. r pharmaceutical properties.

Anotherobject of the invention istot-proyide, chemical compounds. possessing valuable; sympatholytic-properties, which can be, administered orallyias welh asainjection.

A further object-is to provide chemical compounds which are effective in blockingtthe sympathetic-nervous system as well as injected epinephrine and which may. be administered orallyx'as wel-I; astibyt injection; for these purposes.

Other objects including the provision of a method of making the novel compounds will be apparent -from a consideration of this specification and the claims,

In copending. applications of AIlSflI -B Swain, Serial Numbers 327,043 and, 327,945, "both filed December 19, 1952, are disclosed and claimed compounds related to those of the present invention as well as the method of preparing them, and reference may be made, if desired, to said copending applicatious, asamplifyingthe present disclosure;-

The novel" compounds Off th 'PEesent inyention are N,N-"-'bi's(benzodioxanylmethyl) ethylenedi'amine compounds having the following fundamentah structural formula:

, i iinibl s t aharemnlyapartially ial. a m is y Elia-CH 2,695,294 Patented Nov. 23, 1954 2'. ofihydrogen; alkyl' groupscontaining; from 1 to 3' carbon atorng;'benzodioxanylmethyk groups having the structure 'ice and where R2 and Rs are selected from the group consisting of hydrogen, methoxy, and alkyl groups containing from 1 to 4 carbon atoms.

The compounds of the. present invention may be symmetrical or unsymmetrical, that is. to say, in the formula given above, the, R and R1 groups may be identical or may be different, and the R2 and M groups maybe. identical or difierent. Appropriate methods of preparing the symmetricaland unsymmetrical compounds are: set forth hereinafter. In addition, the exact position of the R2, R3, and} R4. groups, when alkyl or methoxy,-*on the. benzene ring portion of the benzodioxanylmethyl groups is notqcri'tical and they may be on the 5, 6, 7, or 8; position, or the product may even be madenuptofi' amixture of compounds differing as to the position of-th'eRz, R3, and. R4 groups.

A's.stated-, the R and. R1 groups in the above structural formulamaytbe. hydrogen: or alkyl groups containing from. 1, .to 3 carbon atoms, that is methyl, ethyl, n-propyl, and isorpropyl. Either one or both of R and R1 may also be a benzodioxanyhnethyl group whereRa is hydrogen, a methoxy group, or an alkyl group containing from 1 to 4 carbon atoms, that is methyl, ethyl, n-pro'pyl, iso-propyl, allyl, n-butyl, secbutyl, and tertiary butyl. When. R and R1 are both benzodioxanylmethyl groups, they may be difierent or the same. In addition, when either or each of R and R1; s a hen edioxauy me up, s group or groups rriay'co'rrespond, tofone or both of the benzodioxanyll' roups of the fundamental structural formula or eir therefrom. The R2 and R3 substituents on th 'benzo dioxanylmethyl; groups of the fundamental til formula aresellected from the same groups me y hxd gen, m th xy a he ky g ps cont g fromfli to4 carbon atoms.

preferredcompounds from the standpoint of as s, 4,.

I 2... highest sympath'olytic activity are those in which, in the above formula, R and R1 join through a dimethylene linkage (CH2CH2--) to complete the piperazine gasses;

treatment of hypertension. .Moreover, the compounds can readily be administered orally without being toxic or producing other deleterious physiological effects, and are effective for the stated purposes when so administered. The compounds will 'range in activity from that of prior available sympatholytic agents to an activity many times greater. In this connection, the preferred group of compounds discussed above possess activity up to about ten times that of sympatholytic agents available commercially prior to the invention when administered parenterally, and, when administered orally, up to twenty to fifty times that obtained upon oral administration of prior agents.

In the compounds of the present invention, there are two basic nitrogens to which one or two equivalents of acid may be added to form a mono or di-salt. Hence, the compounds of the invention may be prepared and/ or employed either as the base or as a salt. Thus, for example, the structural formula for the dihydrochlorides of the compounds of the present invention may be written as follows:

In view of the fact that the salts dilfer from the bases only in the addition of the acid to one or both of the nitrogen atoms referred to and are characterized by the same fundamental structural formula, the salts'as well as the bases are included within the scope of this application and of the claims wherever reference is made to compound comprising the stated structure.

The acid forming the salt may be any inorganic or organic acid desired, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, and the like; acetic, propionic, caproic, stearic, and other acids of this series, and the like; crotonic, oleic, oxalic, citric, tartaric, lactic, benzoic, naphthoic, picric, salicylic, dilituric, methane sulphonic, camphor sulphonic, and the like. If a salt is to be administered, any toxicity which may be imparted by the acid should be taken into consideration as well known in the art.

The compounds of the invention are readily prepared by condensing two moles of an appropriate benzodioxanylmethyl derivative having alkylating properties with one mole of an appropriate ethylenediarnine providing the desired group:

CHr-CEh and for the benzodioxanylmethyl derivative by:

CH2 (EH-CHzX where R and R1 are as hereinabove defined, where R corhowever, R2 and R3 are to be different, the alkylation reaction can be carried out in two steps, by first reacting one mole of diamine compound with one mole of a ben zodioxanylmethyl derivative containing the desired R2, and then reacting the resulting product with one mole of another benzodioxanylmethyl derivative containing the desired R3. In this connection, it may be desirable to block, during the first reaction step, one of the nitrogen atoms of the diamine compound so that the first benzodioxanylmethyl derivative selectively attaches to the other nitrogen atom. Following the first step, therefore, the blocking group may be removed as by hydrolysis and the resulting product subjected to the second reaction step with the second benzodioxanylmethyl derivative. Examples of such a blocking group are the carbalkoxy groups, such as the carbethoxy group (C2H5OOC).

Following the principles outlined above, compounds in which R and/or R1 is a benzodioxanylmethyl group or groups may be prepared. For example, an ethylenediamine compound may be reacted with three or four molar equivalents of benzodioxanylmethyl derivatives either at one time or in several steps depending on the nature of the particular compound desired, and such technique, when R and/ or R1 is to be a benzodioxanylmethyl group or groups, is the equivalent and included within the description set forth in the paragraph before the immediately preceding paragraph.

The reaction between the diamine compound and the benzodioxyanylmethyl derivative may be carried out in alkaline aqueousor alcoholic medium. When an aqueous medium is employed, the alkali used is advantageously sodium hydroxide, and when an alcoholic medium is employed, the alkali used is advantageously sodium carbonate. -It is desirable to heat the reaction mixture until the reaction is complete, and in this connection refluxing is preferred. After the reaction is as complete as desired, the product may be conveniently separated from the reaction mixture by removal of part or all of the solvent used, or byfiltration if the product is a solid. If the product is liquid, it may be removed by extraction with a suitable solvent such asether. In isolating the product, it may be desirable to recover it as a salt and this may be accomplished by treating the reaction product or an extract thereof with a suitable acid of the type discussed hereinabove.

The'following examples serve to illustrate further the present invention.

Example I cooled. The separated solid. is collected, washed first responds to the hereinabove-defined R2, R3 and R4, and

where X is selected from the group consisting of chlorine, bromine, iodine, sulfate, and phosphate, preferably chlo rine or bromine.

Where, in the final product, R2 and R3 are torbe identical, the two moles of benzodioxanylmethyl derivative can be made up of a single compound and these reacted simultaneously with the diamine compound. Where,

with water and then-'with methanol, and dried. Crystallization from a mixture of chloroform and methanol gives white crystals melting from 162-167" C. The calculated analysis for CzzHzsNzOr is C, 69.0; H, 6.9; N, 7.3. That found by analysis is C,'69.0; H, 6.9; N, 7.1.

--.,.'The compound is N,N-bis(1,4-benzodioxan-2-ylmethyl)'-piperazine' and has the structure:

I CH: GET-CH2 C 2 )bn-oHr-N swear-b5 O I ,CHz-C 2 0 Example II A mixture of 66.4 g. (0.309 gram mole) of a mixture of the 5-methoxyand S-methoxyderivatives of 2-chloromethyl-1 ,4-benzodioxan, 29.9 g. (0.154 gram mole) of piperazine hexahydrate and 12.4 g. (0.309 gram mole) of sodium hydroxide in 35 ml. of water is refluxed for 48 hours and then cooled. The gummy solid which separates is collected, washed several times with water and dissolved in acetone. The addition of 6 normal hydrochloric acid causes the precipitation of the hydrochloride salts. Crystallization of the saltsfrom a mixture of water and methanol gives white crystals melting at 263 C. with decomposition. The calculated N content for catmcnuzos v .4;. hat ound is. 5- e product? is a. mix ure of c mpounds hav ng the t c ur s:

By. using. S-rnethoxy-Z-ehloromethyl-1,4-benzodioxan, 6;methoxy 2-chloromethyl-l,4-benzodioxan, 7emethoxy- 2 chloro'methyl-1,4-benzodioxan, eindS-methoxy-Z-chlordmethylLd-benz odioxan, respectively, in placeof. the mixture of the 5-methoxyand S-methoXy: derivatives of 2- chloromethyl:1-,4-benzodioxan of this example, thecorresponding N,N-bis(S-methoxy-1.,4-benzodioxan 2yimethyi )'piperazine; N .N-bis 6-meth0xy- 1,4-ben Zodioxan-2 ylmethyDpiperazine; N,N bis(7-me thoxy-l ,4-benzodioxad-ZfylmethyDpiperazine, and N,N' bis( 8-methoxy-l ,4 b'en zgdioxan-lylfnethyl)piperazine, respectively, are pre- Pare,

Following the same. procedure, but. using a, 5 6 7-., or 8-methyI-2-chloromethyl-l,4-benzodioxan in place of the corresponding methoxy compounds, the corresponding N,N-bis(S-methyl-i,4-benzodioxan-Z-ylrnethy Dpiperazine; N,N bis(6-methyl-1,4-benzodioxan 2-ylmethyl)- piperazinej N,N-bis(.7-methyl-1,4-behzodioxanZ-yimethyl)piperazine, and N',N'-bis(8-methyl-1,4:bnzodioxan2- ylmethyDpiperaxine are prepared. Likewise by usingv the ethyhZ-chloromethyl-1,4rbenzodioxans, the. corresponding; N,Nf-bis (ethyl-1AbenxodibxanQ-ylrnethyl)pipera i s. Ja b p epar d mixtures.o hle. eth r QthYlrZ-ChlOl'QlTlfltilYi-1,,4-bel1zqdiQX2lhS are used, theprod; net; will. be a mixture like that described. 'for the methoxy compounds above.

Example III A mixture of 6.3 g. (0.1 gram mole).o 95% et ylenediamine, 37.0 g. (0 ;2Tgram mole) of 2 -chloromethyll',4- be'n zodio'x an, and 8 g. (0.2 gram mole) of sodiurnhydroxide in. 25 ml. of Water is 'heatedat 110-115? C. for 25 hours. After cooling, the reaction mixture is-diluted with water and extracted with ether. Treatment of the ether layer with hydrogen chloride causes a. solidto separate. Recrystallizationof this solid from a mixture. of methanol andlether gives the dihydrochloride salt of N,N-,"-bis (1,4- benzodioxa'nQ-ylmethyl) ethylenediamine. The calculat'e'dIN content for C25H26C12N204 is 6.5;,that;found is 613 Thecompoundhasthe formula:

y o w na Pie e .mes t n d nExampl 1in connection with thisexample, the corresponding N,N'- bis( methylel,4-benzodioxan-2-ylmethyl)-, N;N-bis( ethyll,4:benzodioxan-Z-ylmethyl) and N,N'-bis(n1ethoxy-l,4- nzqd xane r 'lm t l ns eft se-po n u s r p ep ed.

' By reactingfour molarequivalents. of thel chloromethrl 4.:h bx n k k q i; mst xxder at ye her l W he. pr es qndin .N'-.Nfq eki compound m -h prep ed- The N,N,N-tris(benzodioxan-Z-ylmethyL}. compounds 6 a be pr pa e y emplo ne an ni l. blo k n task.-

f u l st at d Examp e 1 and I I- tie -emitter set forth.

x mal L A mixture of v 10. .0 5v amm N; f-d methylethylenediamine dihydrochloride, 24.0; g 0-13 gram mole); of; 2-chloromethyl-1,4-benzodiox and 19.4 gram. mole): ofs d m hydrox e n= 1 1-. o water is refluxed for 48 hours, cooled, diluted with water and extracted with ether, The ether layer; is extracted several times with. an equal volume of 6' normal hydro chloric acid- The acid extract is neutralized with potassium carbonate andv extracted with ether. After drying, theether extract is treated with anhydrous hydrogen chloride. 'The white solid which separates is collected'and recrystallized from a mixture of methanolv and. ether yielding white crystals which melt at 227 C. with decomposition. The calculated. N. content for C22H3oCi2N2O4 is 6.1; that found is 6.2. The compound has the formula:

Followingthe procedure outlined in Example II in con; motion with. this, example, the corresponding N,N bis; methyll,4-benzodioxane2-ylmethy1) .-N,Nf-dimethylethylenediamine, N,Nf-bis(ethyl-1,4-benzodioxan-2-ylmethyl)-N N-dimethylethylenediamine and N,N'-.bis(methox'y-1,4-benzodioxan-2-ylmethyl) -N.,N'-dimethylethylenediamine compoundsare prepared.

Example V Following the procedure outlined in ExampleIV, but using N, N-diethylethylenediaminedihydroohloride. in place of the. N,N-dimethyiethylenediaminedihydrochloF ride, the corresponding N,N'bis(1,4-benZodioxan-2-ylmethyl)-N,Ni-diethylethylenediamine compound is prepared; The white crystals melt at 212- C with decomposition. The calculated Ncontent for C24I-L34CI2N2O4JS 5;8; that.found is 5.7; Thecompound has theformula;

O\ CH3 CH3 /0 CH2 (1112 $132 CH2 I 21101 H-CH N N-oHi- E 0 CH2G 2 o Following the procedure outlined in Example II in connection with this example, the corresponding N, N-bis- (methyl-1,4-benzodioxan-Z-ylmethyl)'-N, N-diethy1ethylenediamine, N,N bis (ethyl 1,4-benzodioxam2-ylrnethyl) -N. N"-diethyle thylenediamine and N, I Nf-bis (methoxy- 1,4 benzodioxan 2-y1methy1)-N, N'-diethylethylenediamine compounds are prepared. By substituting N,,Nfdipropyl-ethylenediamine dihydrochloride for the N; N'- diethylethylenediamine dihydrochloride, the. correspond ns N p op et yl n dia ne. o po nds. r prepared.

Example VI Following the procedure outlined in. Example IV, but using N-ethy'lethylenediamine dihydrochloride in place of N, N -dhnethyle thylenediaminedihydrochloride, the; cor, responding; N, N-bis( l,4-ben odioxan 2-ylmethyl) Ns ethylethylenediamine, salthaving the; formula V is prepared, as.may: be thecorrespondingN; Nt-biflmetlryl;-. 1,4-benzodioxana2 y1methyl) N=ethy1ethylenediamine traded with diethyl ether.

.alkylor methoxy compounds N,N bis(ethyl 1,4 benzodioxan-Z-ylmethyl) -N-ethylethylenediamine, and N,N-bis(methoxy-1,4-benzodioxan- 2 ylmethyl) N-ethylethylenediarnine compounds. By substituting N-methylethylenediamine dihydrochloride, N-methyl-N'-ethylethylenediamine dihydrochloride, N- propylethylenediamine dihydrochloride, N-propyl-N- methylethylenediamine dihydrochloride, or N-propyl-N- ethylethylenediamine dihydrochloride, respectively, for the N,N-dimethylethylenediamine dihydrochloride of Example IV, the corresponding N,N'-bis(benzodioxan-2- ylmcthyl) N-methyl-ethylenediamine, N,N'-bis(benzodioxan 2 ylrnethyl)-N-methyl-N-ethylethylenediamine, N,N' bis(benzodioxan 2-ylmethyl) -N-propylethylenediamine, N, N'-bis(benzodioxan-Z-ylmethyl)-N-propyl-N- methylethylenediamine or N,N bis(benzodioxan-2-ylmethyl) N-propyl-N'-ethylethylenediamine compounds, respectively, are prepared.

Example VII One mole of piperazine hexahydrate and one mole of 2-chloromethyl-1,4-benzodioxan are refluxed in the presence of one mole of anhydrous sodium carbonate in methanol for 64 hours. After filtration and removal of the solvent, the residue is washed with water and ex- Addition of anhydrous hydrogen chloride to the dried ether solution causes a solid to separate. Recrystallization of this solid from a mixture of acetone and ether gives the monohydrochloride of N-(1,4-benzodioxan-2-ylmethyl)piperazine. The calculated analysis for C13H19C1N202 is Cl, 13.1; N, 10.4. That found by analysis is Cl, 13.4; N, 10.3.

Alternatively, this compound is prepared from its N- carbethoxy derivative by hydrolysis in potassium hydroxide-methanol solution, working the hydrolysate up in a manner similar to that just described. The N'-carbethoxy derivative is obtained by heating together two moles of N-carbethoxypiperazine and one mole of 2-chloromethyl-l,4-benzodicxan at 100 C. for 32 hours. Dilution of the mixture with ether precipitates carbethoxypiperazine hydrochloride, which is removed by filtration. Addition of anhydrous hydrogen chloride to the filtrate precipitates a solid. Recrystallization of this solid from a mixture of methanol and ether gives the hydrochloride of N-(l,4 benzodioxan- 2 -ylmethyl)-N'-carbethoxypiperazine melting at 235 C. The calculated analysis for C1sH23C1N204 is Cl, 10.34; N, 8.18. That found by anaylsis is Cl, 10.50; N, 8.16. The compound has the structure:

Hydrolysis of this compound gives N-(1,4-benzodioxan-2-ylmethyl)piperazine monohydrochloride melting at 197 C. and showing no depression in melting point when mixed with the compound prepared by reaction of fi-chloromethyl-1,4-benzodioxan and piperazine hexahyrate.

This N-(1,4-benzodioxan-2-ylmethyl)piperazine monohydrochloride may be condensed with 2-chloromethyl-l,4- benzodioxan to give the compound of Example I, or with -methyl-2-chloromethyl-l,4-benzodioxan to give N-(5- methyl 1,4-benzodioxan- 2 -ylmet l1yl)-N'-(1,4-benzodioxan-2-ylmethyl)piperazine, or with 5-methoxy-2- chloromethyl-1,4-benzodioxan to give N-(5-methoxy-1,4-benzodioxan- 2 -ylmethyl)-N-(1,4-benzodioxan- 2 -ylmethyl)- piperazine. Similarly, the use of 6-, 7-, or 8-alkylor methoxy compounds gives the corresponding products, that is where R2 in the fundamental structural formula is hydrogen and R3 is an alkyl group containing 1 to 4 carbon atoms or a methoxy group.

By using 5-methyl-2-chloromethyl-1,4-benzodioxan instead of the 2-chloromethyl-1,4-benzodioxan in the first step of this example, the corresponding N-(5-methyl-1,4- benzodioxan 2 ylmethyl)piperazine hydrochloride may be obtained. Condensing this with 5-methoxy-2-chloromethyl-1,4-benzodioxan gives N-(5-methyl-1,4-benzodioxan- 2 -ylmethyl)-N'-(5-methoxy-1,4-benzodioxan- 2 y1methyl)piperazine. In a similar manner, the 6-, 7-, 8-

can be obtained. That is '8 where, in the fundamental structural formula, R2 is' an alkyl group containing from 1 to 4 carbon atoms or a methoxy group and R3 is a methyl group.

If N-(S-methoxy-l,4-benzodioxan-2-ylmethyl)piperazine hydrochloride is condensed with 8-methoxy-2-chloromethyl-1,4-benzodioxan, the product is N-(S-methoxy- 1,4-benzoclioxan- 2 -ylmethyl)-N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)piperazine, a component of the mixture whose preparation is described in Example 11, represented by the third formula given under that example. Similarly, the other unsymmetrical piperazine compounds included within the generic fundamental structural formula may be prepared according to the procedure of this example.

Example VIII One mole of ethylethylenediamine is heated with one mole of Z-chloromethyl-l,4-benzodioxan and one mole of sodium hydroxide in water for 16 hours. The cooled reaction mixture is extracted with ether and the extract is treated with dilute hydrochloric acid. The acid layer is made alkaline with potassium carbonate and extracted with ether. The dried ether solution is treated with anhydrous hydrogen chloride and the precipitated solid is crystallized from a mixture of acetone, methanol, and ether and finally from methanol alone to give the dihydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-N- ethylethylenediamine. The calculated N content for C13H22C12N2O2 is 9.1; that found is 8.8. Alternatively, the reaction may be carried out in the presence of anhydrous sodium carbonate in methanol by the procedure of Example VII; or by hydrolysis of the corresponding N'-carbethoxy derivative.

Condensation of N-(1,4-benzodioxan-2-ylmethyl)-N'- ethylethylenediamine dihydrochloride with one mole of 2- chloromethyl-1,4-benzodioxan gives N, N-bis(l,4-benzodioxan-Z-ylmethyl)-N-ethylethylenediamine, the compound whose formula appears in connection with Example VI. Using 5-methyl-2-chloromethyl-1,4-benzodioxan instead of 2-chloromethyl-1,4-benzodioxan gives N-(5- methyl-1,4 benzodioxan- 2 -ylmethyl)-N-ethyl-N'-(1,4- benzodioxan-Z-ylmethyl)ethylenediamine. Similarly, 5- methoxy-2-chloromethyl-1,4-benzodioxan gives N-(S- methoxy-1,4-benzodioxan- 2 -ylmethyl)-N-ethyl N'-( 1,4- benzodioxan-Z-ylmethyl)ethylenediamine. Use of the 6-; 7-, or 8-alkylor methoxy derivatives gives the corresponding products.

By using S-methyl-Z-chloromethyl-1,4-benzodioxan instead of 2-chloromcthyl-1,4-benzodioxan in the first step of this example, the corresponding N-(5-mcthyl-l,4-benzodioxan-Z-ylmethyl)-N'-ethylethylenediamine may be obtained. Condensing this with 5-methoxy-2-chloromethyl-1,4-benzodioxan gives N-(5-methoxy-l,4-benzodioxan 2 ylmethyl)-N-ethyl-N'-(5-methyl-1,4-benzodioxan-Z-ylmethyl)ethylenediamine. In a similar manner, use of S-methoxy-Z-chloromethyl-1,4-benzodioxan in the first step gives N-(S-methoxy-1,4-benzodioxan-2-ylmethyl)-N'-ethylethylenediamine which, when condensed with S-methyl-Z-chloromethyl-1,4-benzodioxan gives N- (S-methyl-1,4-benzodioxan-2-ylmethyl)-N-ethyl- N -(5- methoxy-1,4 benzodioxan- 2 -ylmethyl)ethylenediamine. Use of the 6-, 7-, or 8-alkyland methoxy derivatives gives the corresponding products.

By substituting ethylenediamine; N, N-dimethylethylcnediamine', N, N-diethylethylenediarnine; N, N-dipropylethylenediarnine; N-methylethylenediamine; N-ethyl- N'-methylethylenediamine; N-propyl-N-methylethylenediamine; or their carbethoxy derivatives for the N-ethylethylenediamine in the first reaction, the corresponding products may be obtained.

Example IX A mixture of 22.6 g. (0.1 gram mole) of a mixture of the S-allyland 8-allyl-derivatives of 2-chloromethyl-l,4- benzodioxan, 9.7 g. (0.05 gram mole) of piperazine hexahydrate and 4.0 g. (0.1 gram mole) of sodium hydroxide in 15 ml. of Water is heated at C. for 48 hours. The reaction mixture is diluted with water and extracted with ether. Addition of 6 normal hydrochloric acid to the ether extract causes a solid to separate. Crystallization of the solid from a mixture of methanol and ether gives white crystals melting at 246 to 249 C. The calculated N content for CzsHssClzNzQa is 5.2; that found 15 5.3. The product is a mixture of compounds having the structures CHr-CH:

orr-om-N CHa CHr-CH:

H QH N Example X Following theprocedure outlined in Example IX, but using a mixture of the 6-allyland 7-allylderivatives of 2-chloromethylbenzodioxan, a mixture of the 6,6'-diallyl-, 3

7,7'-diallyl-, and 6,7'-diallyl derivatives is prepared. The white crystals melt at 262 C. with decomposition. The calculated N content for C2aH3sClaN204 is 5.2; that found is 5.2. The product is a mixture of compounds having the structures A mixture of 16.5 g. (0.0685 gram mole) of a mixture of the 6-tert. butyland 7-tert. butylderivatives of 2- chloromethyl-1,4-benzodioxan, 6.7 g. (0.0342 gram mole) of piperazine hexahydrate and 2.7 g. (0.0685 gram mole) of sodium hydroxide in 3 ml. of water is heated at 110 C. for 52 hours. The reaction product. is diluted with water and extracted with ether. The residue remaining after evaporation of the ether from the ether extract is crystallized from a mixture of acetone and water to give an oil and a White solid. Crystallization Q1 the solid from a mixture of 1,4-dioxan and water gives, white crystals meltigg at160-161 C. The calculated N content f0! CsoH4zNgO4 55 is 5.6; that found is 5.4. The product is a mixture of the 6,6'-, 7,7'-, and 6,7 -di-tertiary butyl derivatives of N,N- bis( 1,4 benzodioxan 2 ylmethyl)piperazine having the formulae:

0 O \CHQ R R1 C tau 1 0 CHz-C: O

(EH-CH2-N where R and R1 are selected from the group consisting of hydrogen, alkyl groups containing from 1 to 3 carbon atoms, benzodioxanylmethyl groups.

H-CHrand a joined dimethylene linkage -CH2-CH2-- to complete the piperazine ring I GE's-CH2 OHz-Cz and where R2, R and R4 are selected from the group consisting of hydrogen, methoxy and alkyl groups containing from 1 to 4 carbon atoms.

2. N,N bis(l,4 benzodioxan 2 ylmethyl) piper-azine compounds having the fundamental structural formula:

0 CH2 CHz-C H2 C lH-CHr-N N-CHr- H O CHr-CH: O

3. N,N' bis(methoxy 1,4 benzodioxan 2 yl methyl) piperazine compounds having the fundamental structural formula:

CH: CHa-CH: C H36 O 4} O CH;

H-CHa-N N-CHz- H O H:- H: O

4. N,N bis(1,4 benzodioxan 2 ylmethyl) ethylenediamine compounds having the fundamental structural formula:

H-CHr-NH S. N,N bis(1,4 benzodioxan 2 ylmethyl) N,N'- dimethylethylenediamine compounds having the fundamental structural formula:

6. N,N' bis(methyl 1,4 benzodioxan 2 ylmethyl) ethylenediamine compounds having the fundamental structural formula:

No references cited. 

1. N,N'' - BIS(BENZODIOXANYLMETHYL) ETHYLENEDIAMINE COMPOUNDS HAVING THE FUNDAMENTAL STRUCTURAL FORMULA: 